Nearly a decade ago, a group of cancer experts met to advise the U.S. Food and Drug Administration on whether to approve a new drug for rare types of leukemia and lymphoma in adults and children.

The drug caused severe reactions in the brain and nervous system, and a small clinical trial found that in more than 75% of children it did not produce the desired response.

Indeed, there was no proof that the drug, nelarabine (Arranon), kept children or adults alive any longer or that it improved their quality of life.

How Low?

At the meeting, Thomas Fleming, PhD, a University of Washington professor of biostatistics and an expert on cancer clinical trials, noted the limited number of children who had a favorable response to the drug.

"How low is the bar for us to say this is something that patients really need to have access to?" asked Fleming, according to a transcript of the meeting.

Despite the concern, the FDA approved nelarabine in 2005. The drug, which GlaxoSmithKline charges about $23,000 a month for, was approved based on a surrogate measure, contingent on a follow-up study to determine if it improved survival.

But 9 years after its approval, that study is not complete. Results are not expected until the end of 2016.

GlaxoSmithKline spokeswoman Bernadette King said the study is the largest trial yet conducted for children with T-Cell acute lymphoblastic leukemia and is being done with the Children's Oncology Group, a premier research group supported by the National Cancer Institute.

While the FDA says it prefers to see high response rates in the drugs it approves based on surrogate measures, low-response-rate drugs such as nelarabine also get on the market. Part of the reason, the agency says, is a lack of alternatives for people with life-threatening cancers.

The poster child for success in the battle against cancer is imatinib (Gleevec), a drug approved based on a surrogate in 2001 to treat a relatively rare disorder, chronic myeloid leukemia.

Imatinib does improve overall survival in leukemia with the first solid evidence of that benefit published in 2006, but more than 10 years would pass before final confirmation of that benefit.

But then there are drugs such as clofarabine (Clolar), manufactured by Sanofi and approved in 2004.

Clofarabine was linked to four deaths during its testing, according to an FDA review. It was approved based on a surrogate measure, and a follow-up study was ordered to determine if there was a survival benefit.

Information on the FDA's website indicates that the follow-up trial of clofarabine, which costs about $36,000 a month, had been scheduled to be completed in 2019. But the agency determined the study did not have a realistic chance of showing clinical benefit and asked that a new plan be submitted.

Sanofi spokeswoman Carrie Brown said the company has been working with the FDA to resolve the issue. She said clofarabine was approved because it showed "meaningful response rates" in patients who had relapsed or whose other treatment had failed at least twice.

"Clolar was the first new FDA-approved therapy to help these children in over a decade," she said. "For many young patients, Clolar is a last resort."

The Long Game

The long wait for study results that show real benefits has turned some cancer experts into skeptics about a drug approval process based on surrogate measures.

In 2012, Mark Levis, MD, director of the leukemia program at Johns Hopkins University, was a member of an FDA advisory panel that was considering approving a new leukemia drug.

When the discussion turned to nelarabine and clofarabine, Levis expressed doubts about the drugs and the approval process.

"I have doled those drugs out for the last 5 years with great glee, and I haven't cured anybody with them," Levis told other panel members, according to a transcript of the meeting. "I'm still waiting on how to use them."

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.